Why do mountains kill some people--or make them so ill they may wish they were dead--while leaving others quite unscathed?

Greg Child recalls vividly his first brush with altitude sickness. It was 1983, and he and his climbing partner were nearing the summit of Broad Peak, a 26,400-foot mountain in northern Pakistan. Suddenly Child was struck by an excruciating headache and a deep, overwhelming desire to sleep. His face began to twitch uncontrollably; his eyes would focus only erratically; his hands balled into fists so tight he could no longer grip his ice ax. The 36-year-old professional climber had never felt anything like it.

Child was probably suffering from the early stages of cerebral edema--literally brain swelling--due to an accumulation of fluid in brain tissues. But the guy I was with, a physician, did even worse, recalls Child. He got profound pulmonary edema--his lungs just filled with fluid. As a physician he was quite aware of what was happening to him. We started down, and I recovered pretty quickly. But on a big mountain like that you can’t descend very fast, and we couldn’t get down fast enough for him. He died that night on the mountain.

High altitudes have humbled even the fittest, most experienced, most macho of climbers. And they’ve been doing so, it seems, ever since humans got the urge to go up mountains. Chinese documents from around 30 B.C. describe a Great Headache Mountain, where men’s bodies become feverish, they lose color and are attacked with headache and vomiting. In A.D. 403 the Chinese chronicler Fa-Hsien traveled to Kashmir and Afghanistan. While ascending a mountain pass, he later recounted, a companion fell violently ill, foaming at the mouth; eventually he died of what probably was the first documented case of high-altitude pulmonary edema.

Yet clearly, not everyone is equally susceptible to altitude problems. In the sixteenth century, Moguls fighting on the Tibetan plateau at elevations of 13,000 to 15,000 feet were struck by mysterious, often lethal illnesses while the Tibetans, to the Moguls’ chagrin, seemed to escape these problems. Today the descendants of those Tibetans, who include the Himalayan Sherpas, continue to live at elevations that can kill other mortals.

Last November, as part of a project to study how they cope with living at such great heights, six Sherpas were flown from Kathmandu to the University of Wisconsin hospital in Madison. The six appeared baffled when asked about the effects of altitude, conversing and laughing among themselves before pausing to let their interpreter answer. They don’t know why they don’t get sick, the interpreter said, adding in jest: They say that mountain people get sick when they go down to hot places.

Different people, different stories. But why? The root cause of the calamity that struck Child and his friend is simple enough: lack of oxygen. Not that the percentage of oxygen in air drops with increasing altitude--it remains constant at about 21 percent. But decreasing barometric pressure lowers the density of the air. That’s why baseball’s rookie Colorado Rockies are such prodigious home-run hitters on their home field; at 5,280 feet, the altitude of Denver, there are 17 percent fewer molecules in the air to slow the flight of a baseball. Unfortunately that also means there are proportionally fewer oxygen molecules to breathe. The higher you go, the more the air thins. At 29,028 feet, the summit of Mount Everest, the lungs get just over a quarter of the oxygen they’re accustomed to.

What does this lack of oxygen do to the average human being? How do our bodies attempt to cope with it? Why does it sometimes cause fluid to seep into the brain or lungs, drowning the body in its own fluids? And why do Sherpas and other people living at high elevations seem largely protected from its effects? One possibility is that people who spend their lives in the mountains are simply super-acclimatized to their environment. Move them away from their mountains and they would soon lose their unusual proficiency and become much more like the rest of us. But recent experiments suggest that something more intriguing might be going on: that these people have made--and perhaps are still making--fundamental changes in their genes to deal with their harsh environment.

Altitude sickness can catch the unwary by surprise, even at ski- resort elevations of around 8,000 to 10,000 feet. By some estimates a quarter of the 25 million tourists who visit Colorado each year come down with at least mild symptoms (with the result that the Colorado ski industry loses some $50 million a year because people feel too crummy to buy $40 lift tickets, gulp $10 hamburgers, and swill $5 beers). The classic case is a skier, hot to hit the slopes, who flies from Chicago to Denver, drives straight from the airport to Keystone, and starts pounding down the diamond runs. Next morning he awakes with what feels like the mother of all hangovers, as if he’d partied to excess the night before. But chances are he’s suffering from the sudden onset of acute mountain sickness.

Acute mountain sickness is typified by a headache that feels as if Thor himself is hammering your brain and by a strong desire to barf. When magnetic resonance images were taken of climbers stricken on Mount McKinley in Alaska in the 1980s, they showed that small amounts of fluid had somehow leaked from the bloodstream and accumulated in the brain. Just how this occurs is the subject of debate. Some people think that with less oxygen available, the energy-intensive process that controls salt and water traffic in cells may run out of gas, so to speak, and start to falter. Others think the brain’s blood vessels may dilate so much in an attempt to get more oxygenated blood to the tissues that the overstretched vessels start to leak. Whatever the reason, the fluid seems to trigger headaches by putting pressure on the brain and perhaps causes dizziness and nausea as well by squeezing blood flow to the cerebellum (at the top of the brain stem), which controls functions such as balance.

Acute mountain sickness won’t kill you--you may just feel so lousy that you wish you were dead. But the condition can be a harbinger of worse to come. The physiological stress that causes it can also lead to high-altitude pulmonary edema and high-altitude cerebral edema. Pulmonary edema can strike at 9,000 feet and up; as the lungs fill with fluid, victims become increasingly short of breath and often spit up foamy blood, as Fa-Hsien’s companion did long ago. Cerebral edema usually hits at 10,000 feet and up. Like acute mountain sickness, it’s caused by water in the brain tissues. In this case, though, enough accumulates to swell the brain inside its rigid, bony box, putting it under enormous pressure. Victims typically lose their motor skills and may stagger and slur their words like a drunk. Some experience vivid hallucinations. (Climbers have reported ascending the peaks with phantom partners and seeing images of Marilyn Monroe on the walls of their hospital room. Child recalls a climber who stumbled down a Himalayan glacier convinced he was walking through a tobacco plantation.) In severe cases, both pulmonary and cerebral edema can kill.

With a bit of care, though, most lowlanders can avoid serious trouble and adjust to thin air. The body tries to cope with low oxygen in several ways, all designed to make the most of what little oxygen there is to fuel its organs and tissues. Initially, for example, breathing steps up to capture more oxygen, and the heart beats faster to pump more oxygen- carrying blood around the body. Later, to increase the blood’s oxygen- carrying capacity, the body makes more of the red blood cells that hold on to oxygen in the bloodstream. Other adaptations take place in the tissues themselves. One of the more obvious is an increase in the small granular bodies, called mitochondria, that float in our cells. Mitochondria--often called the cells’ batteries--transform oxygen and nutrients (principally glucose) into usable energy. This oxidation process, carried out by relay teams of enzymes, produces adenosine triphosphate--ATP--the fuel that powers all our cellular activities.

Thanks to such changes, healthy people can usually cope with altitude--provided they don’t rush the adjustment process. I learned a lot from that first experience, says Child, who in 1990 climbed K2 (at 28,250 feet, the world’s second-highest peak). That’s when I realized the importance of a really long period of acclimatization. Child pulls from his satchel a copy of a book he’s written on his experiences, titled, appropriately enough, Thin Air, and turns to a page charting his big climbs. The one recording his disastrous Broad Peak ascent forms a sharp, upsweeping curve; a record of a successful expedition up Gasherbrum IV (about eight miles, as the crow flies, from Broad Peak) shows a line steadily stepping upward as the climbers made camp at gradually higher altitudes. That’s what you want to do, he says in an accent redolent of his native Australia. You want to go up in plateaus. You know when you’re ready--you stop feeling nauseated and getting headaches. Still, even climbers who work patiently at acclimatizing themselves never feel great, never feel as well and energetic as they do at sea level. Yet between 12,000 and 16,000 feet--well above the point when most lowlanders are feeling serious altitude effects--several populations thrive. How?

Today the Sherpas, who live in the mountainous valleys of Solo and Khumbu in northeastern Nepal, are helping answer that question. Their remote valleys are very far indeed from Madison, where the tallest thing for miles around is the white dome of Wisconsin’s state capitol. In Nepal the six Sherpas participating in the university’s study live in small villages near Namche Bazar, portal to the Everest region, where they work as trekking guides. But last November they came to Madison to be examined with the University of Wisconsin’s positron emission tomography (PET) scanner, which can take detailed pictures of the body’s interior by detecting the presence of radioactive tracers. The study hoped to answer a fundamental question: Have Sherpas changed their metabolism to deal with altitude?

Like most good questions, this one operates at several levels. In recent decades a number of studies have documented the ability of Sherpas and other mountain dwellers, such as the Quechua Indians of Peru, to easily outbreathe and outhike the European and American trekkers who have taken to clambering over the world’s highest peaks. (One Sherpa, Sundare, has reached Everest’s summit a record five times.) But is their superior performance due to conditioning--a temporary adaptation--or to evolution? The notion that humans may have continued to evolve to meet particular conditions, while seemingly straightforward and even intuitively obvious, is not one that everyone feels comfortable with. To some the idea raises the unpalatable specter of genetic determinism. If you accept that one race or ethnic group has a greater ability to thrive in cold or high places, the next thing you know, people will be saying some groups do math or run a business better than others.

As it is, altitude research itself has had its share of racial controversy. In 1925 British physiologist Joseph Barcroft wrote that all dwellers at altitude are persons of impaired physical and mental powers-- presumably because they lived on less oxygen. This drew a sharp response from the visionary Peruvian physician and researcher Carlos Monge, who shot back that Barcroft himself was suffering from altitude sickness when he made the charge. In the 1940s Monge launched his own studies focusing on the Quechua, descendants of the Incas who have lived high in the Andes for thousands of years. He was among the first to theorize that some high- altitude dwellers have evolved in response to their living conditions. But working in the Andes with the primitive tools of the day, he was unable to offer proof that this had occurred.

In the Wisconsin studies, however, Peter Hochachka, a metabolic biochemist at the University of British Columbia, is using the full force of late-twentieth-century technology to study how mountain dwellers get their energy in low-oxygen conditions. Next to the brain, the heart is the body’s biggest energy consumer, but unlike the brain, which uses glucose only, the heart uses fat as well. When glucose isn’t superabundant (after a night without food, for instance), the average person’s heart typically burns fat for energy so that all the glucose in circulation can be saved for vital brain work.

At high altitude, however, that strategy doesn’t work as well because fat is a less efficient fuel to burn when oxygen levels are low. So, Hochachka postulated, people who have adapted to low oxygen levels may have altered their biochemistry. Precisely because glucose is a more efficient fuel than fat, it’s by far the better one to burn when oxygen is limited. Thus, Hochachka reasoned, mountain people might have hearts with a higher preference for glucose, while their brains have developed a tolerance for somewhat lower glucose levels. In 1991 he and his colleagues conducted a study of six Quechua--men who work on the mountain railroads and live at 13,000 feet and up--that suggested he was on the right track. Indeed, a just-completed analysis of the Quechua data has revealed that not only do the Quechua’s hearts prefer glucose but their brains use on average 14 percent less glucose--and therefore less oxygen. It’s as if their brains were saying, ‘I’m going to extend the length of time I can go on a given amount of oxygen by down-regulating my demand for it,’ says Hochachka. Spurred by the Quechua study, he arranged to study a Sherpa group last November.

As planned, the Sherpas underwent two sets of PET scans, one within hours of their arrival in Madison, the other a month or so later, before they headed home. (The idea was to see if their metabolism changed after several weeks at sea level--a way to see if they were merely well acclimatized or if something more fundamental and genetic was going on.) The first subject was Nima Nuru, a compact young man. In a quiet, dimly lit room, Nima Nuru was carefully positioned inside a doughnut-shaped PET scanner, and glucose was injected into his right arm. The glucose had been altered, however, with molecules of fluorine 18, a radioactive tracer, replacing some of its constituent molecules. This counterfeit, radioactive glucose circulated in Nima Nuru’s bloodstream and was taken up by organs using energy, with most taken up by such vital workhorses as the brain and heart. But the mitochondrial enzymes whose job it is to transform glucose into energy weren’t fooled. The enzymes look at the molecule and say, ‘This is not glucose,’ says Jim Holden, a medical physicist at the University of Wisconsin who ran this experiment. So the molecule can’t go through with the process of being oxidized for fuel. Instead it stops, and the radioactivity it emits--in the form of positrons--can be measured. The resulting data were then translated into an image on a video monitor in an adjacent room.

Hunched over the video monitor, Holden eagerly watched for the results. The first pictures to appear were those of Nima Nuru’s heart. At first the radiolabeled glucose injected into his bloodstream seemed to explode inside the chambers of his heart, turning the image bright red. We’ll lose that, explained Holden. And if there’s significant glucose uptake, we’ll get a picture of the heart’s muscular wall. Sure enough, in a few minutes, seven snapshot-size pictures, cross-sectional slices of the heart, appeared on the monitor. And slowly, after the first glow of the fluorine dissipated, you could make out a fiery horseshoe--the muscular wall of Nima Nuru’s left ventricle, the heart’s main pumping chamber, as it absorbed the tracer glucose and gave off the telltale positrons. Later he was repositioned in the scanner, and similar scans were taken of his brain.

Though the brain data have yet to be analyzed, the heart results were clear. Like the Quechua, the Sherpas showed a strong preference for glucose over fat for fuel when they were hungry, a distinct advantage at altitude. What’s more, as subsequent experiments showed, the Sherpas--like the Quechua--exhibited what is called the lactate paradox, which has puzzled physiologists since it was first reported 50 years ago by Monge.

Humans burn glucose in two ways--anaerobically (without oxygen) and aerobically. The anaerobic method produces lactate, the stuff that makes your muscles gripe when you do too many sit-ups. Burning glucose anaerobically is not very efficient--you get 18 times more energy doing it with oxygen. But it might be expected that the Quechua or Sherpas, given their low-oxygen environment, would rely on it heavily. Quite the contrary. Blood tests show that during exercise the Quechua and Sherpas produce less lactate than would be expected. Somehow the enzymes in their mitochondria that control metabolism have developed a way to use oxygen more efficiently, keeping the aerobic energy pathway open far longer than in a sea-level dweller. Most intriguing of all, these unusual traits remained stable during the five weeks that the Sherpas and the Quechua spent in North America. (In contrast, after a climbing trip, lowlanders lose their acclimatization in less than a month.)

Confirmation of a genetic adaptation? Not quite yet. Perhaps Sherpas kept in the plains for a year would have much the same physiology as a resident of Chicago (a city that impressed them deeply during their visit). It’s not proof--just a hint of an unusually long-term adaptation that could be genetic, says Hochachka. Until he and similarly interested researchers can prove their case, however, the dominant view remains that mountain people are much like the rest of us: it’s just that because of a life spent at high altitude, they’ve developed a substantial but quite temporary ability to thrive at 10,000 feet. Even the Sherpas and their Tibetan relatives have their limits; there are no permanently inhabited villages above 17,000 feet anywhere in the world.

Nonetheless, evidence in favor of evolution is beginning to accrue. One of the more tantalizing clues is that Tibetans who have lived in the Himalayas for 20,000 years, at least twice as long as the Quechua have lived in the Andes, have more and better adaptations than the Indians. That not only suggests that the Tibetans’ adaptations could be genetic, it hints that the Quechua could still be in the process of evolving. It’s almost as if the Quechua haven’t caught up with the Tibetans, who have had longer to adapt to their harsh Himalayan environment, according to Lorna Moore, an anthropologist at the University of Colorado at Denver, who has spent the past ten years researching the Tibetans’ adaptations.

In one particularly telling project, Moore and colleagues at the Tibet Institute of Medical Sciences in Lhasa looked at the effects of altitude on pregnancy. Altitude usually has a harsh impact on pregnancy, resulting in smaller babies and increasing women’s susceptibility to a dangerous form of high blood pressure--called preeclampsia--that can lead to seizures and sometimes death. Prior studies suggested that women prone to such problems didn’t increase their breathing sufficiently to compensate for low oxygen levels.

Moore compared 30 Tibetan women with 30 Han Chinese, an ethnic group from the lowlands that has lived in Tibet for only 20 to 30 years. Among Tibetans living at 12,200 feet the average baby weighed 7.5 pounds, the same as American babies born at sea level. Babies born to Han women were a whole two pounds smaller.

Moore suspected that the Tibetan mothers’ ability to supply oxygen to their unborn babies made the difference. But contrary to expectation, she found that Tibetan women had lower oxygen levels in their blood than Han women. Rather than breathing more, Tibetan women sent proportionally more oxygen to their babies by diverting more blood to the womb. Moore was able to ascertain this by using an ultrasound device, developed by a colleague, that measures the Doppler shift of moving blood-- a sort of sonar gun for blood cells. This allowed her to noninvasively record the speed with which blood flows through vessels--and the faster it flows, the greater the volume. You can demonstrate mathematically that a 10 percent increase in blood flow has a greater impact on fetal oxygen supply than a 10 percent increase in breathing, says Moore. So the Tibetans were selecting a strategy that was more efficient.

Moore and her colleagues have shown a number of other ways that the Tibetans are better adapted than the Han Chinese. For example, Tibetans have a very high capacity for exercise due to greater lung volume and unusually efficient hearts. And far fewer Tibetan than Han babies die during their first year from subacute infantile mountain sickness, an illness caused by failure of the right side of the heart. Each time we’ve peeled off the covering and investigated the relevant phenomenon, we found that the Tibetans differed from the Han and that they were better off, says Moore. In some cases, as with the mothers and newborns, these differences seem to make the Tibetans better adapted in the evolutionary sense--because they have more surviving offspring, Tibetans are better able to reproduce and get their genes into the next generation. Moreover--and intriguingly--when she and her colleagues looked at the adult offspring of Tibetan women and Chinese men, they found that their breathing and exercise capacity placed them directly between pure Tibetans and Han--another potential hint of genes at work.

Still, the real proof that the Tibetans or other mountain people have developed particular genetic traits is elusive. To clinch their case, Moore, Hochachka, and other altitude researchers would have to link such advantageous traits with actual pieces of gene. There are so few physiological functions that are understood from a genetic standpoint, says Moore. It’s like looking for a needle in a haystack. Still, says Holden, that search is now under way, with researchers particularly looking for genetic variations in proteins involved in our body’s use of oxygen-- such as hemoglobin, which binds oxygen to carry it in our blood.

Lest these questions sound arcane, it’s worth remembering that ultimately altitude studies--studies on how humans cope with lack of oxygen--focus on the central process of life. The lungs, heart, and arteries exist in large part for one function: shuttling oxygen to the brain. Any breakdown in that system can lead to death within minutes. We’re probing secrets that nature has worked out for dealing with a problem that is clinically very important, says Hochachka. Stroke and cardiac arrest remain the West’s dominant killers. And both result from a sudden cutoff of oxygen to vital organs--to the brain and to the heart. So the more we can learn about how healthy Sherpas and Tibetans defend these critical organs against low supplies of oxygen, the better. Should research, for example, find that Tibetans have genes that control their blood pressure when pregnant, it may be possible to relate that finding to the treatment of lowlanders with hypertension--a major predisposing factor for heart disease and stroke. Once you’ve located the protective genes, you could think about gene therapy, or replicating the genes’ effects with drugs.

But beyond the practical potential, confirming that mountain dwellers have developed unique, enduring ways to cope with their low-oxygen environment would add a big piece to the puzzle of human evolution. Sometimes, as a species, we set ourselves apart and assume that we have left our biological heritage behind--that our success and survival are not subject to such earthly matters as environmental pressure, observes Moore. This would tell us that humans are continuing to adapt, just like other species.